Human Molecular Genetics Advance Access published online on June 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn176
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PTHR1 MUTATIONS ASSOCIATED WITH OLLIER DISEASE RESULT IN RECEPTOR LOSS OF FUNCTION
1 INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3; Université Paris 7, UFR Médicale, 75018 Paris, France 2 Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, B-1348 Brussels, Belgium 3 AP-HP, Hôpital Bichat Claude Bernard, Service de Biochimie hormonale et génétique; Université Paris 7, UFR Médicale, 75018 Paris, France 4 Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires St Luc, 10-1200 Brussels, Belgium
* Address correspondence to: Caroline Silve M.D., PhD INSERM U561 et centre des maladies rares du calcium et du phosphore Hôpital Saint Vincent de Paul 84 avenue Denfert Rochereau, 75014 Paris, France tel: 33 1 40 48 80 17 fax: 33 1 40 48 83 40
Received April 24, 2008; Revised June 14, 2008; Accepted June 14, 2008
PTHR1 signalling pathway is critical for regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease / Maffucci's syndrome, two developmental disorder defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1 signalling pathway in Ollier disease and Maffucci syndrome, we analysed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function, either by reducing the affinity of the receptor for PTH or reducing receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in 5/31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.
5 Present address: INSERM U561, Hôpital Saint Vincent de Paul, 84 avenue Denfert Rochereau, 75014 Paris, France. 84 avenue Denfert Rochereau, 75014 Paris, France email: Caroline.Silve{at}inserm.fr tel: 33 1 40 48 80 17 fax: 33 1 40 48 83 40